The objective of this research project is to identify the inducers and suppressors of the urea cycle enzymes in mammalian liver, and to elucidate the mechanisms by which enzyme induction is accomplished. Eventually, such inducers may make it possible to control the levels of these enzymes in human liver. Control mechanisms operative in the arginine biosynthetic pathway of microorganisms will be sought for in mammalian cells and compared with the role of hormones as inducers or suppressors. The experimental systems to be employed are: a) monolayer cultures of rat liver cells; b) rats; c) tissue of humans with genetic or acquired deficiencies of urea cycle enzymes. The specific aims of the project are as follows: 1) Define whether glucagon and cyclic AMP induce the urea cycle by effects on transcription or translation of genetic information. 2) Determine whether glucagon and cyclic AMP induce by increasing synthesis and/or by decreasing degradation of the enzymes. 3) Assess the roles of other hormones as inducers or suppressors, and for permissive, additive or synergistic interactions with glucagon. 4) Test whether amino acids which induce the cycle have direct effects on liver cells or are effective in proportion to their abilities to release glucagon, insulin or other hormones. 5) Study genetic urea cycle deficiencies in hyperammonemic children, acquired enzyme deficiencies in children with Reye's syndrome and acquired deficiencies in cirrhosis of the liver.